The intent of the work presented in this proposal is to counter the worldwide health problem brought on by the spread of chloroquine-resistant malaria. To address the need for an orally available and inexpensive replacement drug, we have developed a novel class of molecules called "reversed chloroquines" (RCQs) which act against both chloroquine-resistant and chloroquine-sensitive malaria. Herein we describe a new sub-class of RCQ molecules, which we term branched RCQ (bRCQ) molecules. These bRCQ molecules may be even better than the 'simple' RCQs. The goal of the described project is to understand how to optimize structural features in the bRCQ molecules to yield the best possible, orally available drug against malaria. This will be accomplished by producing a panel of varied bRCQ structures, and then testing them against chloroquine-sensitive and chloroquine-resistant malaria in red cell culture (an in vitro test), as well as for solubility, central nervous system receptor activity, and cytotoxicity. The most promising candidates will then be evaluated as orally available drugs against malaria in mice. Once these experiments demonstrate the feasibility of the bRCQ molecular design, as well as provide fundamental understanding of correlations between molecular features and efficacy of bRCQs against malaria, the bRCQ structures will be "tuned" in order to optimize practical aspects of their use in humans. Although we are directing this study specifically against P. falciparum, the most problematic human malaria variant, bRCQs should also be effective against the other human malarias. Although there may be a very thin profit margin to be had some 'endemic markets', there is an increasing ability to pay for drugs in countries such as India and China and the military and traveler markets have promise for reasonable commercialization. [unreadable] [unreadable] [unreadable]